Activation of complement, a key component of innate immunity, results in generation of anaphylatoxins that are pleiotropic effector molecules that mediate inflammatory processes such as chemoattraction, vasodilation and vasopermeability (Markiewski et al. 2007 Am J Pathol 171: 715-727), and non-inflammatory processes such as tissue regeneration, lipid metabolism, and synapse formation (Klos et al. 2009 Mol Immunol 46: 2753-2766). Activation of complement terminates in formation of a pore on the surface of target cells referred to as the membrane attack complex (MAC), resulting in cell lysis and cell death.
Inappropriate activity of the complement system, specifically on endothelial cells, results in a number of diseases and negative conditions. Damage and detachment of the endothelium due to abnormal complement activity has been documented in atypical hemolytic uremic syndrome, aHUS (Zipfel et al. 2001 Trends Immunol 22: 345-348). Membranoproliferative glomerulonephritis (MPGN) MPGN type I and MPGN type II (dense deposit disease) are characterized by presence of complement proteins within the subendothelial dense-deposit along the glomerular basement membrane (Pickering et al. 2008 Clin Exp Immunol 151: 210-230). Dense deposit disease has been linked to a deficiency in complement regulator, Factor H (Licht et al. 2009 Thromb Haemost 101: 271-278). Transgenic mice expressing negative regulator of complement protectin (CD59) on the endothelium are protected against atherosclerosis (Wu et al. 2009 Circ Res 104: 550-558).
Age-related macular degeneration (AMD) is a disease associated with aging that gradually destroys sharp, central vision, and is the leading cause of blindness in the elderly (Klein et al. 2007 Ophthalmology 114: 253-262). The macula is a specific tissue located in the center of the retina, the light-sensitive tissue at the back of the eye that converts light or an image into electrical impulses.
AMD is classified as either wet age-related macular degeneration or dry age-related macular degeneration. Wet AMD is characterized by growth of abnormal blood vessels behind the retina under the macula. These new blood vessels are fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal place at the back of the eye, causing loss of central vision. Wet AMD is treated with laser surgery, photodynamic therapy, and injections into the eye. None of these treatments, however, cures wet AMD, rather the treatments slow progression of the disease. Dry AMD is characterized by slow breakdown of light-sensitive cells in the macula, gradually blurring central vision in the affected eye. Over time, less of the macula functions and central vision is gradually lost. There is no known form of treatment for advanced stage dry AMD, and vision loss is inevitable. A specific high-dose formulation of antioxidants and zinc has been shown to prevent intermediate stage AMD from progressing to advanced AMD.
AMD has been tightly linked to polymorphisms in various complement genes (Anderson et al. 2010 Prog Retin Eye Res 29: 95-112), and complement proteins such as MAC have been observed to be deposited on choroidal endothelial cells (Anderson et al. 2002 Am J Ophthalmol 134: 411-431).
Complement proteins are deposited on the choriocapillaris of patients with diabetic retinopathy, as well as in the retinal vessels of diabetic subjects (Geri et al. 2002 Invest Ophthalmol Vis Sci 43: 1104-1108). These vessels also exhibited significant reduction in expression of the complement regulatory proteins decay accelerating factor (CD55) and CD59. Hyperacute rejection of organ transplantation, mainly the liver and kidney, has shown evidence of complement activity on the endothelium, and is considered a key reason for transplant rejection (Satoh et al. 1997 Transplantation 64: 1117-1123). An ex vivo perfusion simulation of xenotransplantation using normal human blood in porcine liver was associated with intralobular hemorrhage and complete loss of hepatic function within hours of complement component 3 and MAC deposition on endothelial cells (Pascher et al. 1996 Transplant Proc 28: 754-755).
There is a need for systems, methods and kits for assaying (i.e., prognosing or diagnosing) ocular diseases and retinal pathologies such as AMD and for identifying potential therapeutic agents. Currently, no effective methods are available for treating complement-diseases or conditions, let alone AMD. There is a need for compositions, methods and kits for preventing or treating a subject having a complement-related condition.